In this study of the vaginal flora of 171 pregnant women in labor at term, the flora was categorized as normal (Lactobacillus predominant), intermediate, or representative of bacterial vaginosis (BV) on the basis of a vaginal smear. BV was diagnosed in 39 women (23%); the vaginal flora was classified as normal in 50% of cases and as intermediate in 27%. H2O2-producing lactobacilli were recovered from 5% of women with BV, 37% of those with an intermediate flora, and 61% of those with a normal flora. H2O2-negative lactobacilli were equally frequent (57%-65%) in all three groups. The microorganisms most frequently recovered from women with BV included Gardnerella vaginalis, Prevotella bivia/disiens, Bacteroides ureolyticus, Prevotella corporis/Bacteroides levii, Fusobacterium nucleatum, Mobiluncus species, Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus anaerobius, viridans streptococci, Ureaplasma urealyticum, and Mycoplasma hominis (P < .05 for each). The presence of all but three of these organisms was inversely related to vaginal colonization by H2O2-producing lactobacilli; the exceptions were B. ureolyticus, F. nucleatum, and P. prevotii. Other microorganisms were equally frequent among women with and without BV. We conclude that specific groups of anaerobes are associated with BV in this population and that a strong association exists between species associated with BV and those inhibited by H2O2-producing lactobacilli.
Gardnerella vaginalis is associated with a spectrum of clinical conditions, suggesting high degrees of genetic heterogeneity among stains. Seventeen G. vaginalis isolates were subjected to a battery of comparative genomic analyses to determine their level of relatedness. For each measure, the degree of difference among the G. vaginalis strains was the highest observed among 23 pathogenic bacterial species for which at least eight genomes are available. Genome sizes ranged from 1.491 to 1.716 Mb; GC contents ranged from 41.18% to 43.40%; and the core genome, consisting of only 746 genes, makes up only 51.6% of each strain's genome on average and accounts for only 27% of the species supragenome. Neighbor-grouping analyses, using both distributed gene possession data and core gene allelic data, each identified two major sets of strains, each of which is composed of two groups. Each of the four groups has its own characteristic genome size, GC ratio, and greatly expanded core gene content, making the genomic diversity of each group within the range for other bacterial species. To test whether these 4 groups corresponded to genetically isolated clades, we inferred the phylogeny of each distributed gene that was present in at least two strains and absent in at least two strains; this analysis identified frequent homologous recombination within groups but not between groups or sets. G. vaginalis appears to include four nonrecombining groups/clades of organisms with distinct gene pools and genomic properties, which may confer distinct ecological properties. Consequently, it may be appropriate to treat these four groups as separate species.
Background Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. Methods MTN-013/IPM 026, a multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative U.S. women, evaluated vaginal rings containing dapivirine (25 mg) and maraviroc (100 mg), dapivirine-only, maraviroc-only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. Results There was no difference in related genitourinary adverse events between treatment arms compared to placebo. Dapivirine and maraviroc concentrations rose higher initially before falling more rapidly with the combination ring compared to relatively stable concentrations with the single drug rings. Dapivirine concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. Maraviroc was consistently detected only in CVF. Dapivirine and maraviroc CVF and dapivirine tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and dapivirine levels. Conclusions In this first study of a combination microbicide vaginal ring, all four rings were safe and well tolerated. Tissue dapivirine concentrations were 1,000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. Dapivirine, but not maraviroc, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Since maraviroc concentrations were consistently detectable only in CVF and not in plasma, improved drug release of maraviroc rings is needed.
Lactobacilli colonizing the rectum may be a reservoir for vaginal lactobacilli. In a cross-sectional study of 531 females, vaginal and rectal colonization by lactobacilli were assessed by culture methods. A subset of isolates was identified to the species level by use of whole-chromosomal DNA probes. Lactobacillus crispatus (16%), L. jensenii (10%), and L. gasseri (10%) were the prevalent lactobacilli colonizing the rectums of 290 females. Only 13 (9%) of 147 females colonized by L. crispatus or L. jensenii vaginally and/or rectally had bacterial vaginosis (BV), compared with 12 (44%) of 27 females colonized by other H(2)O(2)-producing lactobacilli (P < .001). Cocolonization of the vagina and rectum by H(2)O(2)-producing lactobacilli was associated with the lowest prevalence of BV (5%), whereas females colonized only vaginally, only rectally, or at neither site had a successively increased risk of BV (P < .001). Lactobacillus species in the rectum may contribute to the maintenance of vaginal microflora.
ObjectivesSuccessful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo.MethodsHIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1∶1∶1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint.ResultsAll 36 subjects enrolled completed the 7–14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration.ConclusionsSingle and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538)
A healthy vaginal ecosystem has been shown to be protective against the acquisition of human immunodeficiency virus and gonorrhea, and women who are colonized with H 2 O 2 -producing lactobacilli are more likely to maintain a normal vaginal flora than women with lactobacilli that do not produce H 2 O 2 . The purpose of this study was to formulate a testing medium that better supports the growth and detection of H 2 O 2 by a broader range of lactobacilli than a published, widely used agar formulation (TMB). The new medium (TMB-Plus) consists of brucella agar base, 3,3,5,5-tetramethylbenzidine, horseradish peroxidase, starch, vitamin K, hemin, magnesium sulfate, manganese sulfate, and horse serum. To validate the new formula, 256 vaginal isolates and ATCC strains were inoculated onto TMB-Plus and, for comparison, onto TMB. Growth was enhanced for 69% of the isolates on TMB-Plus, and 48% had enhanced color production. The percentage of H 2 O 2 -positive isolates increased from 71% on TMB to 79% on TMB-Plus. Formulations using Rogosa or MRS agar base in combination with peroxidase and a chromogen did not support the growth of all of the strains of Lactobacillus, and fewer H 2 O 2 -producing strains were detected on these formulations than on TMB-Plus. This new medium better supports the growth of a wider range of Lactobacillus strains isolated from the vagina and enhances the color production of H 2 O 2 -producing strains.While production of lactic acid has been widely considered to be the factor which allows Lactobacillus spp. to dominate the vaginal ecosystem, more-recent data suggest that H 2 O 2 production by lactobacilli may be more relevant than lactic acid production. In a recent study of 101 women monitored over 8 months, 96% of women who maintained colonization by the same species of Lactobacillus were colonized by H 2 O 2 -producing strains of Lactobacillus crispatus or L. jensenii. In contrast, only 1 of 21 women who lacked H 2 O 2 -producing strains remained colonized by lactobacilli over the same period (19). Bacterial vaginosis, a condition characterized by reduced numbers of vaginal lactobacilli, has been associated with an increased risk of acquisition of human immunodeficiency virus (16), while the absence of vaginal Lactobacillus spp. is associated with increased acquisition of human immunodeficiency virus and gonorrhea (9). Women vaginally colonized by H 2 O 2 -producing strains of lactobacilli are only half as likely to acquire bacterial vaginosis as women colonized by lactobacilli that do not produce H 2 O 2 (7).Several methods have been used to detect production of H 2 O 2 by lactic acid bacteria or macrophages. The assays are generally based on the oxidation of a chromogen that works as a hydrogen donor by a horseradish peroxidase-H 2 O 2 complex, which results in a color or fluorescence change depending on the chromogen used. The methods used to quantitate H 2 O 2 production require growth of the organism or cells in a broth culture, testing by addition of a chromogen and horseradish peroxida...
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